Steroid-resistant nephrotic syndrome is an autosomal recessive disease that manifests as focal segmental glomerulosclerosis with onset during early childhood, progression to end-stage renal disease and absence of recurrence after transplantation. Phenotypic variability in the renal manifestations of steroid-resistant nephrotic syndrome has been reported in recent cases in the literature. An animal model of SRNS in which the Nphs2 gene has been inactivated by homologous recombination has revealed strain differences, highly suggestive of genetic modifiers. We propose to identify modifier loci that determine and influence the rate of progression of renal failure in nephrotic syndrome. We also propose to inactivate Nphs2 in a tissue-specific and temporally controlled fashion in mice. This new model should enable us to address the genetic mechanisms underlying the pathogenesis of proteinuric renal failure, as well as establish the importance of podocin in the function of the mature glomerulus. The results of this proposal will have broad implications not only to our understanding of this disease, but also to similar disorders where the renal glomerulus is the focus of injury.